Cerebrospinal fluid eosinophils in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Eosinophils in cerebrospinal fluid (CSF) are an uncommon finding most often associated with parasitic infections, but have also been described in some neuroinflammatory disorders. Eosinophilic infiltration is not thought to be a typical feature of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). We aim to describe the rate of CSF eosinophil positivity in a cohort of pediatric MOGAD patients. METHODS: Single-center retrospective chart review of pediatric MOGAD patients. Clinical and laboratory data was collected from the electronic medical record and analyzed. RESULTS: Of 46 pediatric patients with positive serum myelin oligodendrocyte glycoprotein antibody (MOG-IgG) identified, 38 patients fulfilling internationally proposed MOGAD diagnostic criteria were included for analysis. 6 patients with MOGAD were excluded as no CSF data was available, and 2 patients with positive MOG-IgG but diagnosis more consistent with MS were excluded. Median age was 7.3 years, and 19/38 (50 %) were female. Acute disseminated encephalomyelitis (ADEM) was the most common presenting phenotype (23/38, 61 %), and other phenotypes included optic neuritis (10/38, 26 %), transverse myelitis (3/38, 8 %), and neuromyelitis optica spectrum disorder (NMOSD) (2/38, 5 %). 12 of 36 (33 %) patients with all lumbar puncture (LP) data available had CSF eosinophils present, with eosinophil mean of 3 % and range from 1 % to 18 % of CSF while blood cells. CONCLUSION: CSF eosinophils were present in one third of pediatric MOGAD patients, which is a higher rate than previously reported in either MOGAD or aquaporin-4 antibody positive NMOSD cohorts. Understanding the CSF composition of pediatric MOGAD patients helps to facilitate more prompt diagnosis and treatment and may shed light onto underlying pathologic mechanisms of disease with the goal to inform future therapeutic targets.

Longitudinal evaluation of serum MOG-IgG titers in MOGAD after initiation of maintenance immunoglobulin: A case series.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct demyelinating disease of the central nervous system. Immunoglobulin (Ig) has been used as a maintenance therapy to prevent relapses in MOGAD, but the impact of Ig on serum MOG-IgG titers is unclear. OBJECTIVE: To characterize the variation in serum MOG-IgG titers after initiation of Ig treatment in people with MOGAD. METHODS: We conducted a retrospective study of 10 patients with a diagnosis of MOGAD and available serum MOG-IgG titers before and after initiation of maintenance Ig treatment. RESULTS: We found that most of the patients remained MOG-IgG seropositive while on Ig treatment with a reduced or unchanged titer, despite a lack of disease activity. CONCLUSIONS: This case series suggests that the mechanism of action of Ig therapy in MOGAD is not exclusively dependent on MOG-IgG titer reduction.

Nucleic acid biomarkers of immune response and cell and tissue damage in children with COVID-19 and MIS-C.

Differential host responses in coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) remain poorly characterized. Here, we use next-generation sequencing to longitudinally analyze blood samples from pediatric patients with COVID-19 or MIS-C across three hospitals. Profiling of plasma cell-free nucleic acids uncovers distinct signatures of cell injury and death between COVID-19 and MIS-C, with increased multiorgan involvement in MIS-C encompassing diverse cell types, including endothelial and neuronal cells, and an enrichment of pyroptosis-related genes. Whole-blood RNA profiling reveals upregulation of similar pro-inflammatory pathways in COVID-19 and MIS-C but also MIS-C-specific downregulation of T cell-associated pathways. Profiling of plasma cell-free RNA and whole-blood RNA in paired samples yields different but complementary signatures for each disease state. Our work provides a systems-level view of immune responses and tissue damage in COVID-19 and MIS-C and informs future development of new disease biomarkers.

Changes in HDL cholesterol, particles, and function associate with pediatric COVID-19 severity.

Background: Myriad roles for high-density lipoprotein (HDL) beyond atheroprotection include immunologic functions implicated in the severity of coronavirus disease-2019 (COVID-19) in adults. We explored whether there is an association between HDL and COVID-19 severity in youth. Methods: A pediatric cohort (N = 102), who tested positive for COVID-19 across a range of disease manifestations from mild or no symptoms, to acute severe symptoms, to the multisystem inflammatory syndrome of children (MIS-C) was identified. Clinical data were collected from the medical record and reserve plasma aliquots were assessed for lipoproteins by NMR spectroscopy and assayed for HDL functional cholesterol efflux capacity (CEC). Findings were compared by COVID-19 status and symptom severity. Lipoprotein, NMR spectroscopy and CEC data were compared with 30 outpatient COVID negative children. Results: Decreasing HDL cholesterol (HDL-c), apolipoprotein AI (ApoA-I), total, large and small HDL particles and HDL CEC showed a strong and direct linear dose-response relationship with increasing severity of COVID-19 symptoms. Youth with mild or no symptoms closely resembled the uninfected. An atypical lipoprotein that arises in the presence of severe hepatic inflammation, lipoprotein Z (LP-Z), was absent in COVID-19 negative controls but identified more often in youth with the most severe infections and the lowest HDL parameters. The relationship between HDL CEC and symptom severity and ApoA-I remained significant in a multiply adjusted model that also incorporated age, race/ethnicity, the presence of LP-Z and of GlycA, a composite biomarker reflecting multiple acute phase proteins. Conclusion: HDL parameters, especially HDL function, may help identify youth at risk of more severe consequences of COVID-19 and other novel infectious pathogens.

Multicenter Study of the Impact of COVID-19 Shelter-In-Place on Tertiary Hospital-based Care for Pediatric Neurologic Disease.

Objective: To describe changes in hospital-based care for children with neurologic diagnoses during the initial 6 weeks following regional Coronavirus 2019 Shelter-in-Place orders. Methods: This retrospective cross-sectional study of 7 US and Canadian pediatric tertiary care institutions included emergency and inpatient encounters with a neurologic primary discharge diagnosis code in the initial 6 weeks of Shelter-in-Place (COVID-SiP), compared to the same period during the prior 3 years (Pre-COVID). Patient demographics, encounter length, and neuroimaging and electroencephalography use were extracted from the medical record. Results: 27,900 encounters over 4 years were included. Compared to Pre-COVID, there was a 54% reduction in encounters during Shelter-in-Place. COVID-SiP patients were younger (median 5 years vs 7 years). The incidence of encounters for migraine fell by 72%, and encounters for acute diagnoses of status epilepticus, infantile spasms, and traumatic brain injury dropped by 53%, 55%, and 56%, respectively. There was an increase in hospital length of stay, relative utilization of intensive care, and diagnostic testing (long-term electroencephalography, brain MRI, and head CT (all P<.01)). Conclusion: During the initial 6 weeks of SiP, there was a significant decrease in neurologic hospital-based encounters. Those admitted required a high level of care. Hospital-based neurologic services are needed to care for acutely ill patients. Precise factors causing these shifts are unknown and raise concern for changes in care seeking of patients with serious neurologic conditions. Impacts of potentially delayed diagnosis or treatment require further investigation.

Differential activation of neuroinflammatory pathways in children with seizures: A cross-sectional study.

PURPOSE: Inflammation plays a crucial role in epileptogenesis. We analyzed inflammatory cytokines in plasma and saliva from children with seizures and healthy controls and measured their associations with HHV6 and EBV infection. METHODS: We analyzed plasma from 36 children within 24 h of seizures (cases) and 43 healthy controls and saliva from 44 cases and 44 controls with a multiplex immunoassay. Saliva from all controls and 65 cases and blood from 26 controls and 35 cases were also analyzed by PCR for viral DNA. Primary outcome was cytokine levels in cases vs. controls. Secondary outcomes included detection of HHV-6 and EBV viral DNA in cases vs. controls and viral loads in cases vs. controls. Statistical analysis included the Wilcoxon Rank Sum test, Fisher's exact test, ANOVA, and Spearman correlation. RESULTS: Compared to controls, patients had higher levels of CCL11 (p = 0.0018), CCL26 (p<0.001), IL10 (p = 0.044), IL6 (p<0.001), IL8 (p = 0.018), and MIP1ß (p = 0.0012). CCL11 was higher with 3 or more seizures (p = 0.01), seizures longer than 10 min (p = 0.001), and when EEG showed focal slowing (p = 0.02). In saliva, febrile seizures had higher levels of IL-1ß (n = 7, p = 0.04) and new onset seizures had higher IL-6 (n = 15, p = 0.02). Plasma and saliva cytokine levels did not show a correlation. The frequency of HHV-6 and EBV detection was similar across groups and not different than controls. We found no correlation between viral load and cytokine levels. CONCLUSIONS: We showed differential activation of neuroinflammatory pathways in plasma from different seizure etiologies compared to controls, unrelated to viral infection.

SARS-CoV-2-Specific T Cell Responses Are Stronger in Children With Multisystem Inflammatory Syndrome Compared to Children With Uncomplicated SARS-CoV-2 Infection.

Background: Despite similar rates of infection, adults and children have markedly different morbidity and mortality related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Compared to adults, children have infrequent severe manifestations of acute infection but are uniquely at risk for the rare and often severe Multisystem Inflammatory Syndrome in Children (MIS-C) following infection. We hypothesized that these differences in presentation are related to differences in the magnitude and/or antigen specificity of SARS-CoV-2-specific T cell (CST) responses between adults and children. We therefore set out to measure the CST response in convalescent adults versus children with and without MIS-C following SARS-CoV-2 infection. Methods: CSTs were expanded from blood collected from convalescent children and adults post SARS-CoV-2 infection and evaluated by intracellular flow cytometry, surface markers, and cytokine production following stimulation with SARS-CoV-2-specific peptides. Presence of serum/plasma antibody to spike and nucleocapsid was measured using the luciferase immunoprecipitation systems (LIPS) assay. Findings: Twenty-six of 27 MIS-C patients, 7 of 8 non-MIS-C convalescent children, and 13 of 14 adults were seropositive for spike and nucleocapsid antibody. CST responses in MIS-C patients were significantly higher than children with uncomplicated SARS-CoV-2 infection, but weaker than CST responses in convalescent adults. Interpretation: Age-related differences in the magnitude of CST responses suggest differing post-infectious immunity to SARS-CoV-2 in children compared to adults post uncomplicated infection. Children with MIS-C have CST responses that are stronger than children with uncomplicated SARS-CoV-2 infection and weaker than convalescent adults, despite near uniform seropositivity.

Psychological Needs and Services in a Pediatric Multidisciplinary Celiac Disease Clinic.

This study aims to describe the psychological needs in children with celiac disease (CD) and to examine the feasibility of psychological consultation in a multidisciplinary clinic. Participants (N = 69) included children with CD and their parents who completed a pre-clinic mental health survey and a 30-min psychological consultation as part of a multidisciplinary clinic (including gastroenterology, nutrition, education, neurology, and neuropsychology). Quantitative and qualitative analyses examined psychological needs, experiences, and satisfaction. The psychologist identified clinically significant symptoms and provided referrals in 49% of children. There were no significant differences by time since CD diagnosis. During the psychology consultation, families discussed emotional adjustment, impact on life and physical well-being, and management of the gluten-free diet. Parents reported high levels of satisfaction from the clinic visit. We identified frequent psychological needs in pediatric CD. The multidisciplinary approach may be a feasible model for specialized, optimal treatment in this population.

A multi-disciplinary clinic for SCN8A-related epilepsy.

OBJECTIVE: We endeavored to evaluate a cohort of patients diagnosed with SCN8A-related epilepsy in a multi-disciplinary clinic and to create a bio-repository. METHODS: We recruited patients with epilepsy due to SCN8A variants at Children's National Medical Center, through family organizations, or SCN8A.net. Study procedures included medical record review, review of EEG and MRI data, clinical evaluation, the Vineland Adaptive Behavior Scales, Third Edition (VABS-3), DNA extraction, and preparation of peripheral blood mononuclear cells. RESULTS: Seventeen patients (9 months - 19 years) completed the study. Age at seizure onset was 1 day to 4 years old (median age 4 months). Epilepsy phenotype ranged from mild epilepsy to severe developmental and epileptic encephalopathy. Medications targeting the voltage-gated sodium channel were most often effective, while levetiracetam resulted in worsening seizures and/or developmental regression in 7/16 (p < 0.05). VABS-3 scores were below age expectations for most children; older children had lower scores. Neurological examination revealed hypotonia (13), spastic quadriparesis (1), ataxia (9), dyskinesia (2)/ dystonia (7), and four non-ambulatory. CONCLUSIONS: This is the first report of a large series of patients with epilepsy due to SCN8A variants evaluated in a single multi-disciplinary clinic. By utilizing a more comprehensive and consistent evaluation, we clarify specific seizure and epilepsy types, describe a distinct epilepsy phenotype in a patient with a nonsense variant, delineate patterns of developmental delay, language, and swallow function (specifically anomic aphasia and flaccid dysarthria), identify and characterize movement disorders, report common findings on physical exam, and demonstrate clinical worsening with levetiracetam.

A Quantitative Assessment of Gluten Cross-contact in the School Environment for Children With Celiac Disease.

OBJECTIVES: A gluten-free (GF) diet is the primary treatment for celiac disease (CD). Gluten is used in schools, particularly in early childhood, art, and home-economics classrooms. This study aimed to measure gluten transfer from school supplies to GF foods that a child with CD may eat. Also, to measure efficacy of washing techniques to remove gluten from hands and tables. METHODS: Five experiments measured potential gluten cross-contact in classrooms: Play-Doh (n = 30); baking project (n = 30); paper mâché (n = 10); dry pasta in sensory table (n = 10); cooked pasta in sensory table (n = 10). Thirty participants ages 2 to 18 were enrolled. Following activities, gluten levels were measured on separate slices of GF bread rubbed on participant's hands and table surfaces. Participants were assigned 1 of 3 handwashing methods (soap and water, water alone, or wet wipe). Repeat gluten transfer measurements were taken from hands and tables. Gluten measurements made using R-Biopharm R7001 R5-ELISA Sandwich assay. RESULTS: Paper mâché, cooked pasta in sensory tables, and baking project resulted in rates of gluten transfer far greater than the 20 ppm threshold set by Codex Alimentarius Commission. Play-Doh and dry pasta, however, resulted in few gluten transfers to GF bread >20 ppm. Soap and water was consistently the most effective method for removing gluten, although other methods proved as effective in certain scenarios. CONCLUSIONS: The potential for gluten exposure at school is high for some materials and low for others. For high-risk materials, schools should provide GF supplies and have a robust strategy to prevent gluten cross-contact with food.

Mental Health Disorders and Psychosocial Distress in Pediatric Celiac Disease.

OBJECTIVES: Celiac disease (CeD) has been associated with increased mental health disorders (MHD) and psychosocial distress in children, which may complicate treatment with the gluten-free diet (GFD). This single-center cross-sectional study examined psychological comorbidities in children with CeD to assess psychological needs in CeD care. METHODS: Participants were 73 parents (95% mothers) of children (ages 3-18) attending a multidisciplinary celiac disease clinic. Parents completed electronic surveys about their child's MHD history, psychological symptoms, and GFD experiences. Rates of MHD were calculated and compared with National Institute of Mental Health population-level data. Differences in psychosocial symptoms and GFD experiences were examined based on child age, time since CeD diagnosis, and MHD. RESULTS: Thirty-four percentage of children had at least 1 MHD; anxiety disorders (16%, P < 0.001) and attention-deficit/hyperactivity disorder (ADHD; 16%, P = 0.01) were more common than general population rates. More than 1 quarter of parents reported current child psychosocial distress (28%-39%), and approximately half reported parent stress (51%) and financial burden (46%) associated with the GFD. Parents of children with new CeD diagnoses reported lower confidence in the GFD (P < 0.01) but MHD, stress, and financial burden did not differ by time since CeD diagnosis. Children with MHD had more anxiety, anger, overall distress, and parent distress than those without MHD (Ps < .05). CONCLUSIONS: Comorbid CeD and MHD was common and was associated with increased child and parent psychosocial distress. Our findings emphasize the importance of psychological screening and services to assess for and treat comorbid MHD and to mitigate psychosocial distress associated with the GFD.

Fueling the FIRES: Hemophagocytic lymphohistiocytosis in febrile infection-related epilepsy syndrome.

OBJECTIVES: Although secondary hemophagocytic lymphohistiocytosis (HLH) has been reported in children with critical illness of various etiologies, it has not been reported in patients with febrile infection-related epilepsy syndrome (FIRES). We describe a series of patients with concurrent HLH and FIRES in an effort to establish common pathophysiologic abnormalities. METHODS: Five patients with FIRES who were assessed for HLH were identified from a neurocritical care database. All were previously healthy and had extensive diagnostic testing. All had clinical deterioration with multiorgan dysfunction prompting HLH screening 20-29 days after hospitalization. Markers for inflammatory dysregulation were assessed in cerebrospinal fluid (CSF) and serum at various time points. Outcomes were assessed 6 months after presentation. RESULTS: Three patients met clinical criteria for secondary HLH. Elevation of specific cytokines/chemokines was variable. CSF neopterin, high mobility group box 1 (HMGB1), and C-X-C motif chemokine ligand 8 (CXCL8) were significantly elevated in all. Interleukin-1ß (IL-1ß) and IL-18 were not elevated in any of the samples. Treatment and outcomes were variable. SIGNIFICANCE: We describe 3 patients with HLH and FIRES. The co-occurrence of these 2 rare disorders suggests the possibility of a common immune dysregulation phenotype prolonging epileptogenesis. HLH screening in critically ill patients with FIRES may yield a broader understanding of shared inflammatory processes.